New Alzheimer's animal model more closely mimics human disease

December 4, 2017
Upper panel: Tau clumps in new AD mouse model, either in the cell body as neurofibrillary tangles (NFTs) or in dystrophic axons surrounding A-beta plaques as neuritic plaque tau. Lower panel: tau clumps in human AD brain, as NFTs (arrow head) and NP tau. Credit: The lab of Virginia Lee, PhD, Perelman School of Medicine, University of Pennsylvania

By injecting human Alzheimer's disease brain extracts of pathological tau protein (from postmortem donated tissue) into mice with different amounts of amyloid-β (Aβ) plaques in their brains, researchers from the Perelman School of Medicine at the University of Pennsylvania found that amyloid-β facilitates the interaction between the plaques and abnormal tau. This relationship promotes the spread of mutated tau proteins in neurons, which is the hallmark of long-term Alzheimer's disease. They published their findings this week in Nature Medicine.

"Making an AD mouse model that incorporates both Aβ and tau pathologies in a more AD-relevant context has been greatly sought after but difficult to accomplish," said senior author Virginia M-Y Lee, PhD, director of the Center for Neurodegenerative Disease Research (CNDR) at Penn. "This study is a big step for AD research, which will allow us to test new therapies in a more realistic context."

Alzheimer's disease is characterized by Aβ plaques outside cells and clumps of tau within cells. Researchers have proposed that Aβ plaques are the initiating pathology of AD, but the failure of all AD clinical trials based on removing Aβ challenges this hypothesis and the idea of targeting Aβ alone to treat AD. At the same time, evidence from other studies, including research from CNDR, strongly correlates the spread of tau clumps with worsening cognition in AD, but the exact link between the two pathologies has remained enigmatic.

Tau works like railroad track crossties in stabilizing microtubules in axons responsible for transporting material inside neurons. Removal of tau protein from microtubules due to its clumping in nerve cells causes the affected neurons to become dysfunctional, ultimately leading to their death and AD.

The Penn team mimicked the formation of three major types of AD-relevant tau pathology in their new mouse model: neurofibrillary tangles, neuropil threads, and tau aggregates surrounding Aβ plaques, called neuritic tau. "For the first time we could see and study the tau clumps in dystrophic axons surrounding Aβ plaques in a mouse model, just like we see in a human brain with AD," said first author Zhuohao He, PhD, a postdoctoral fellow in Lee's lab.

The team found that Aβ plaques create an environment that facilitates the rapid amplification and spread of pathological tau into large aggregates, initially appearing as neuritic plaque tau. This was followed by the formation and spread of neurofibrillary tangles and neuropil threads to other neurons. These tau protein formations also impaired brain functions, including memory difficulties, in the mice.

This study is the basis for a new way to explain how the Aβ plaque environment accelerates the spread of tau pathology in the brains of AD patients, which is consistent with imaging studies and investigations of postmortem AD brains.

The findings suggest new targets and strategies to treat AD patients. "Our new of AD with both Aβ and tau can now be used to test therapies that target one or both pathologies to see if combination or single-target therapy is better," Lee said.

Explore further: More human-like model of Alzheimer's better mirrors tangles in the brain

More information: Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation, Nature Medicine (2017). nature.com/articles/doi:10.1038/nm.4443

Related Stories

More human-like model of Alzheimer's better mirrors tangles in the brain

November 16, 2016
Tangled up brain fibrils made up of a rogue protein known as tau are the hallmark of Alzheimer's disease (AD) that likely hold the key to treatments, making them of great interest to researchers. Mimicking the formation and ...

Genetically engineered mice suggest new model for how Alzheimer's causes dementia

July 4, 2016
Using a novel, newly developed mouse model that mimics the development of Alzheimer's disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological "insults" must ...

Saving neurons may offer new approach for treating Alzheimer's disease

November 6, 2017
Treatment with a neuroprotective compound that saves brain cells from dying also prevents the development of depression-like behavior and the later onset of memory and learning problems in a rat model of Alzheimer's disease. ...

Scientists reveal role for lysosome transport in Alzheimer's disease progression

August 7, 2017
Researchers from Yale University School of Medicine have discovered that defects in the transport of lysosomes within neurons promote the buildup of protein aggregates in the brains of mice with Alzheimer's disease. The study, ...

Abnormal brain protein may contribute to Alzheimer's disease development

September 30, 2016
A recently-recognized pathologic protein in the brain may play a larger role in the development of clinical Alzheimer's disease dementia than previously recognized, according to a study by researchers at Rush University Medical ...

Single traumatic brain injury may prompt long-term neurodegeneration

July 18, 2011
Years after a single traumatic brain injury (TBI), survivors still show changes in their brains. In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania suggest that Alzheimer's ...

Recommended for you

Dementia with Lewy bodies: Unique genetic profile identified

December 15, 2017
Dementia with Lewy bodies has a unique genetic profile, distinct from those of Alzheimer's disease or Parkinson's disease, according to the first large-scale genetic study of this common type of dementia.

Major cause of dementia discovered

December 11, 2017
An international team of scientists have confirmed the discovery of a major cause of dementia, with important implications for possible treatment and diagnosis.

Canola oil linked to worsened memory and learning ability in Alzheimer's

December 7, 2017
Canola oil is one of the most widely consumed vegetable oils in the world, yet surprisingly little is known about its effects on health. Now, a new study published online December 7 in the journal Scientific Reports by researchers ...

Genetics study suggests that education reduces risk of Alzheimer's disease

December 7, 2017
The theory that education protects against Alzheimer's disease has been given further weight by new research from the University of Cambridge, funded by the European Union. The study is published today in the BMJ.

Healthy mitochondria could stop Alzheimer's

December 6, 2017
Alzheimer's disease is the most common form of dementia and neurodegeneration worldwide. A major hallmark of the disease is the accumulation of toxic plaques in the brain, formed by the abnormal aggregation of a protein called ...

Alzheimer's damage in mice reduced with compound that targets APOE gene

December 6, 2017
People who carry the APOE4 genetic variant face a substantial risk for developing Alzheimer's disease.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.